Adamantanes and tricyclo[4. 3. 1. 1 3.8] undecanes



United States Patent 3,352,912 ADAMANTANES AND TRICYCL0[4.3.1.1

UNDECANES William W. Prichard, Hockessin, Del., assignor to E. I. duPont de Nemours and Company, Wilmington, Del., a corporation of DelawareNo Drawing. Filed June 18, 1964, Ser. No. 376,259 19 Claims. (Cl.260-563) ABSTRACT OF THE DESCLOSURE Cross-reference This application isa continuation-in-part of my copendin application S.N. 297,23 3, filedJuly 24, 1963, now abandoned.

According to the present invention, I have discovered a class of novelcompounds having pharmaceutical ap plication and useful as antiviralagents. They have the ability to inhibit and deter incidence and growthof harmful viruses. Additionally, compounds of this class of compoundsexhibit significant stimulant activity.

The com-pounds of this invention are adamantanes of the formula andtricyclo[4.3.l.l ]undecanes of the formula 3,352,912 Patented Nov. 14,1967 where X and Y can be the same or different and are hydrogen,

methyl or ethyl; and

where n is 2, 3, 4, 5, or 6; NR R or N CHR wherein R is hydrogen; alkylof 1 through 6 carbon atoms; mono-substituted alkyl of 1 through 6carbon atoms where the substituent is hydroxy, alkoxy of 1 through 2carbon atoms, NH NHR or -NR R where R and R can be the same or differentand each is an alkyl radical of 1 through 4 carbon atoms; alkenyl of 2through 6 carbon atoms; alkynyl of 2 through 6 carbon atoms;cyclopropyl; cyclobutyl; cyclopropylmethyl; cyclobutylmethyl;

R is R chlorine; bromine; for-myl; CH COOH or CH COOC H with the provisothat when R is alkenyl or alkynyl having the unsaturated bond in the1-position, R is alkyl or mono-substituted alkyl as above defined; and

substituent is aromatic or heterocyclic; aromatic; or heterocycliccontaining not more than 12 carbon atoms.

Compounds hydrolyzable to the compounds of Formulas l and 2 are for mostpurposes equivalent to those compounds and are of course contemplated aswithin the present invention.

It also will be understood that the compounds within the scope ofFormulas 1 and 2 having a basic amino group, readily form salts and suchsalts having a non-toxic anion are also included within the scope of thepresent invention. Representative of such salts are hydrochlorides,hydrobromides, sulfates, phosphates, acetates, succinates, adipates,propionates, tartrates, citrates, bicarbonates,

pamoates, cyclohexylsulfamates and acetylsalicylates. Of

For example, by proper selection of compounds, it is found that it ispossible to attain different desired balances of stimulant andanti-viral activities as well as different desired balances of drugdynamics and anti-viral activities depending upon the type of diseaseand patient being treated.

Accordingly, compounds of the invention are preferred Where the amine onthe adamantane or undecane moiety is substituted with dialkyl(N,N-dialkylated compounds) because they provide a very favorablebalance of antiviral activity with reduced stimulant activity. Of these,the lower alkyl substituents such as the dimethyl and diethylderivatives are most preferred from considerations of higher anti-viralactivity. Compounds of the invention where the amine on the adamantaneor undecane moiety is monoalkylated also demonstrate reduced stimulantacanti-viral activity than the dialkylated amine derivatives.

R is aliphatic; mono-substituted aliphatic where the zit-substitutedcompounds exhibit higher anti-viral activity but less favorable drugdynamics in comparison to the :,oL-Sllb5iil1lll6d compounds.

In view of. the foregoing considerations, the most preferred compoundsof the invention for pharmaceutical application'are the followingcompounds and their hydrochloride salts:

1- (N,N-dimethylaminomethyl) adamantane 1- N-methylaminomethyl)adamantane 1- N-ethyl-N-methylaminomethyl) adamantane 1-( aminomethyladamantane 1- (MN-diethylaminomethyl) adamantane 1- N-ethylaminomethyladamantane 3 -(N,N-dimethylaminomethyl)tricyclo [4.3 .1.1

undecane 3 -(N-methylaminomethyl)tricyclo[4.3.1.1 ]undecane3-(N-ethyl-N-methylaminomethyl)tricyclo[4.3.1.1

undecane 3 aminomethyl tricyclo [4.3 .1 l ]undecane 3N,N-diethylarninomethyl tricyclo [4.3 1.1 undecane 3-(N-ethylaminomethyl)tricyclo [4.3.1.1 ]undecane a-methyl- 1-adamantanemethylamine a-methyl-3 -tricyclo [4.3 l .1undecanernethylamine a,a-dimethyl-l -adamantanemethylaminea,u-dimethyl-3-tricyclo[4.3 l 1 undecanemethylamine The compounds ofthis invention can be prepared by a variety of methods.

l-adamantane carboxylic acid and 3-tricyclo[4.3.1.1 undecane carboxylicacid can be converted to the corresponding acid chlorides with thionylchloride. The unsubstituted amides and a variety of N-alkylandN,N-dialkylsubstituted amides can be prepared from the acidchlorides byreaction with the appropriately substituted amines and ammonia. Theseamides are then reduced with lithium aluminum hydride to thecorresponding amino-, N-alkylaminoand N,N-dialkylaminomethyl-adamantanes.and tricycloundecanes.

Thea-alkyl-l-adamantanemethylamines and a-alkyl-3- tricyclo[4.3.1.1]undecanemethylamines are prepared by reduction of adamantyl-(l) alkylketone oximes and tricyclo[4.3.1.1 ]undecyl-(3) alkyl ketone oximes withlithium aluminum hydride. The ketones from which these oximes arederived are conveniently made by the reaction of the appropriate dialkylcadmium with l-adamantoyl chloride or 3-tricyclo[4.3.1.1 ]undecoy1chloride.

The u,a-dialkyl-l-adamantanemethylamines and .ot,oL- dialkyl 3tricyclo[4.3.1.1 ]undecanemethylamines are made by the reaction ofacetonitrile and sulfuric acid (Ritter reaction) with the correspondinga,a-dialkyl-1-adamantanemethanol or (1,0: dialkyl 3 tricycl0[4.3.1.l]undecanemethanol, which gives the N acetyl a,ot dialkylladamantanemethylamine or N acetyl 04,0: dialkyl 3 tricyclo[4.3.l.1]undecanemethylamine. The amine is obtained by alkaline hydrolysis. Thestarting alcohols for these reactions are made by the reaction of 1adamantoyl chloride or 3-tricyclo[4.3.1.1 ]undecoyl chloride with alkylGrignard reagents.

A variety of aminescan be used for the preparation ofl-adamantanecarboxamides and 3 tricyclo[4.3.1.1 ]undecanecarboxamides,to give a variety of substituent groups on the nitrogen ofl-(aminomethyl)adamantane and 3-(aminomethyl)tricyclo[4.3.1.1 ]undecane.For example, reactions of the acid chlorides with allylamine anddiallylamine give the N-allyl and N,N-diallyl compounds after reduction.Reactions of the acid chlorides with propargylamine and dipropargylaminegive the N-propargyl and N,N-dipropargy1 compounds after reduction.Reactions with cyclopropylarnine cyclopropylrnethylamine and pyrrolidinegive the N-cyclopropyl, N-cyclopropylmethyl and pyrrolidino compoundsafter reduction. Reactions with alkoxyalkylamines give the N-alkoxyalkylcompounds after reduction. Of course, reactions of the acid chlorideswith amines having difierent N-substituents give correspondingN,N-disubstituted amino compounds. For instance, reactions of the acidchlorides with N-allyl-N- methylamine give1-(N-allyl-N-methylaminomethyl)adamantane and3-(N-allyl-Nrmethylaminomethyl)tricyclo- [4.3.1.1 ]undecane.

Some substituted alkyl amino compounds are more easily made by otherroutes. Hydroxyethyland bis-hydroxyethyl compounds are made by reactionof the amine with ethylene oxide. N-carbalkoxymethylamino compounds aremade by alkylation with alkyl chloroacetate and base.

Aminoalkyl-, alkylaminoalkyl-, and dialkylaminoalkyl compounds are madeby alkylation with appropriate aminoalkyl halides and base, althoughthey can be made by treating the corresponding hydroxyalkyl compoundwith a thionyl halide to replace the hydroxyl group with a halogen andthen replacing the halogen with the amino, alkylamino, or dialkylaminogroup by reaction with ammonia or a primary or secondary amine.

In some cases, N-alkyland N,N-dialkyl-compounds are easily made byalkylation of l-(aminomethyl)adamantane and3-(aminomethyl)tricyclo[4.3.1.l ]undecane with alkylating agents (suchas alkyl halides), without resorting to reduction of N-alkylandN,N-dialkyl-amides.

When the reagents are used in molar amounts, the monoalkylamino compoundis generally formed as the major product, whereas greater amounts of thereagents give the dialkylamino compound. This method is not as clean-cutas reduction of the amides which is Why it is less preferred. However,it sometimes becomes the method of choice because it involves fewersteps.

Ethylene chloroand bromo-hydrin, and alkoxyalkyl halides can be used. toalkylate the amino nitrogen, to give the hydroxyethylandalkoxyalkyl-substitutions. For the reasons just given, these reactionsare less preferable than other methods but. may be preferred in certaininstances, and they illustrate an alternate route to substitutedalkylaminomethyltricyclo[4.3.1.1 ]undecanes and adamantanes by ordinaryalkylation with a substituted alkylating reagent.

Reactions of l-(aminomethyl)adamantane and 3-(aminomethyl)tricyclo[4.3.1.1 ]undecane with aldehydes give thecorresponding alkylidene, arylidene or heterocyclicylideneaminomethyladamantanes and aminomethyltricycloundecancs. For instance,reaction of l-(aminomethyl)adamantane with formaldehyde givesN-(l-adamantylmethyl)azomethine. Reaction of 3-(aminomethyl)tricyclo[4.3.l.l ]undecane with benzaldehyde gives 3-(benzylideneaminomethyl)tricyclo [4.3.1.1 ]undecane.

Reactions of l-(aminomethyl)adamantane. or 3-(aminomethyl)tricyclo[4.3.1.l. ]undecane or the corresponding l-(N-alkylaminomethyl)compounds with butyl formate give the formamido-compounds.

Representative of the compounds of this invention are the followingcompounds and their salts:

1- aminomethyl) adamantane 1- (N-methylaminomethyl) adamantane l-(N,N-dirnethylaminomethyl) adamantane 1- (N-ethyl-N-methylaminomethyladamantane 1- (N,N-diethylaminomethyl) adamantanel-(N-propylaminomethyl) adamantane 1- (N-methyl-N-propylaminomethyl)adamantane 1- (N-isopropylaminomethyl adamantane 1-(N-methyl-N-isopropylaminomethyl) adamantanel-(N,N-diisopropylaminomethyl) adamantane 1-(N-sec-butylarninomethyl)adamantane 1-(N-isobutylaminomethyl) adamantane 1-(N-tert-butylaminomethyl adamantane 1- N-hexylaminomethyl adamantane 1-(N-isoa-mylaminomethyl) adamantane 3 (N-allyl-N-methylaminemethyl)tricycle [4. 3 1 1 undecane 3- (N,N-di-allylaminemethyl tricycle [4.3 11 undecane 3-. [N- (heXen-3 -yl) aminemethyl] tricycle [4.3. 1. 1undecane 3 (N-ethynyl-N-methylaminemethyl) tricycle [4.3 1 1 undecane 3-(N-prepargylaminemethyl tricycle [4.3 1 1 undecane 3-(N,N-di-prepargylaminemethyl) tricycle[4.3.1.1

undecane 3- (N-hydrexyrnethylaminemethyl) tricycle [4. 3 1 .1

undecane 3 -(N-methexymethylaminemethyl)tricyclo[4.3.1.1

undecane 3- (N-ethexymethylarninemethyl tricycle [4.3 1 1 1 undecane 3-[N-(Z-methexyethyl) aminemethyl] tricycle [4.3 1. 1

undecane 3 [N- (Z-hydrexyethyl) anlinemethyl] tricycle [4.3 l 1 3undecane 3- [N- Z-hydrexyethyl) -N-methylaminernethyl] tricycle [4.3.1.1]undecane 3- [N,N-di 2-hydrexyethyl) aminemethyl] tricycle [4.3.1.1]undecane 3- (N-aminemethylarninornethyl) tricycl-e[4.3 1 1 undecane 3-N-aminernethyLN-methylaminemethyl) tricycle [4.3.1.1 ]undecane 3 [N-methylarninemethyl) aminemethyl] tricycle [4.3.1.1 ]undecane 3- [N-butylarninernethyl) aminemethyl] tricycle [4.3 .1.1 undecane 3- [N-(isebutylarninemethyl aminemethyl tricycle [4.3.1.1 ]undecane 3- [N-(sec-butylaminernethyl) aminernethyl] tricycle [4.3.1 1 undecane 3[N-(tert-butylaminernethyl arninomethyl] tricycle [4.3.1.1 ]undecane 3-[N- (dirncthylaminemethyl) aminernethyl tricycle [4.3.1.1 ]undecane 3-[N- (N-butyl-N'-methylarninernethyl) aminemethyl] tricycle[4.3.1.1]undecane 3- [N-dibutylaminernethyl) aminernethyl] tricycle [4.3 .1.1]undecane 3 [N-diisebutylarninernethyl) aminernethyl} tricycle [4.3 .1 1undecane 3 -N- [di( l-methylpentyl) aminernethyl] aminemethyl tricycle[4.3 .1.1 ]undecane 3- [N-(di-tert-butylaminemethyl) aminemethyl]tricycle [4.3 .1.1 ]undecane 3 [N-(6-hydrexyhcxyl) aminemethyl] tricycle[4.3 1 .1

undecane 3 -[N-(3-hydrexyhexyl) aminomethyl]tricycle[4.3.1.1

undecane 3 [N- 6-methexyhexyl) aminemethyl] tricycle [4.3 1.1

undecane 3 [N- (3 -rnethexyhexyl)aminernethyl]tricyclo[4.3.1.1

undecane 3 [N- 6-ethexyhexyl) aminemethyl] tricycle [4.3 1 1 undecane 3[N-( 3 -ethexy-2-rnethylpentyl) aminemethyl] tricycle- [4.3.1.1]undecane 3- [N- Z-amineethyl aminemethyl tricycle [4.3 1.1]

undecane 3- [N- 2-rnethylamineethyl) aminemethyl] tricycle [4.3 .1.1]undecane 3 [N- 3-dirnethylamineprepyl aminemethyl] tricycle [4.3 .1 1undecane 3 [N- (2-dimethylarnineethyl -N-methylaminomethyl] tricycle[4.3. 1 .1 undecane 3 [N-(6-amiuehexyl) aminemethyl] tricycle [4.3 l 1undecane 3- N-( l-amine- 1 -ethylbutyl aminomethyl] tricycle- [4.3.1.1]undecane 3- [N- 6-methylaminehexyl) aminemethyl] tricycle- [4.3.1.1]undecane 3- [N- (4-butylaminohexyl) aminemethyl] tricycle- [4.3.1.1]undecane.

3- [N- 6-isebutylarninehexyl) aminerncthyl] tricycle- [4.3.1. l]undecane 3-N- 6-( l-rnethylpentyl) aminohexyl] aminemethyl tricycle[4.3 .1. 1 ]undecane 3-[N- (6-tert-butylarninehexyl) aminornethyl]tricycle- [4.3.1.1 ]undecane 3- [N,N-di- Z-diethylamineethyl)aminernethyl] tricycle- [4.3.1. l ]undecane 3- [N-6-dirnethylaminehexyl) aminemethyl] tricycle- [4.3.1 1 ]undecane 3- N-3-dimethylarninehexyl)aminemethyl1 tricycle- [4.3.1. l ]undecane 3- N-(6-dibutylaminehexyl) aminernethyl] tricycle- [4.3.1.1 ]undecane 3- [N-6-diisebutylarninehexyl) aminemethyl] tricycle- [4.3.1.1 ]undecane 3-[N- 6-di-tertbutylaminehexyl aminemethyl1tricycle- [4.3 l 1 undecane 3-(N-chlereaminernethyl) tricycle [4.3 .l.1 undecane 3-(N-chlere-N-methylaminemethyl) tricycle [4.3 11

undecane 3- (N-chlere-Nhexylarninemethyl) tricycle [4.3 1 1 undecane 3-(N-bremeaminernethyl) tricycle [4.3.1. 1 ]undecane 3-(N-brome-N-methylaminemethyl tricycle [4.3 .1. 1

undecane 3- (N-brerno-N-hexylaminemethyl) tricycle [4.3 1 1 undecane3-(fermamidernethyl) tricycle [4.3.1.1 undecane 3- (Nrnethylfermarnidemethyl) tricycle [4.3 1 1 undecane 3-(N-hexylfermamidernethyl)tricycle[4.3.l.1

undecane N- (Fr-tricycle [4.3.1. 1 undecylmethyl) glycine N-(3-tricycle[4.3.1.1 ]undecylmethyl) sarcesine N-(3-tricycle [4.3 1. 1 undecylmethyl-N-hexylglycine N-(3-tricycle [4.3.1. 1 undecylmethyl) sarcesine, methylester N-(3-tricycle[4.3.1.1 ]undccylmethyl)-N-hexylglycine,

methyl ester N- 3 -tricycle [4.3. 1.1 ]undecyln1ethyl) glycine, ethylester N-(3-tricycle[4.3.1.1 ]undecylmethyhsarcesine, ethyl ester N-(3-tricycle [4.3 .1 .1 undecylmethyl) -N-hexylglycine,

ethyl ester 3-(benzylideneaminernethyl) tricycle [4.3 .1 1 undecane 3-(ethylideneaminemethyl) tricycle [4.3 1 1 ]undecane 3-isehexylideneaminemethyl) tricycle [4.3 1 1 undecane 3-(naphthylidenearninernethyl) tricycle [4.3. 1 1

undecane 3- (furfurylideneaminemcthyl) tricycle [4.3 .1. 1

undecane N-( 3-tricycle [4.3.1.1 ]undecylrnethyl) aziridine N-3-tricycle [4.3 .1 .1 ]undecylrnethyl) azetidine N- 3 -tricycle[4.3.1.1undecylmethyl)pyrrelidine N-(B-tricycle[4.3.1.1 3]undecylmethybpiperidine N- 3-tricycle [4.3 1.1 undecylmethyl)hexamethyleneimine This invention will be more fully understood byreference to the fellewng illustrative examples in which parts andpercentages are by weight unless otherwise indicated.

Example 1 A solution of 6 parts of I-adamantane carbexamide in 200 partsof tetrahydrefuran is added slowly to a wellstirred suspension of 6.15parts of lithium aluminum hydride in 200 parts of dry diethyl ether.After completion of addition, the mixture is refluxed for one hour andthe solvent distilled 01f. The residue is subjected to steamdistillation. The waxy l-aminomethyl adamantane is extracted from thesteam distillate with ether and the ethereal solution dried with solidpotassium hydroxide. Dry hydrogen chloride is then passed into the ethersolution to precipitate the amine hydrochloride. The yield is 5.25 partsof l-(aminomethyl)adamantane hydrochloride which melts at 337-340 C.after recrystallization from chloroform-benzene.

Analysis.Calcd. for C H NCI: C, 65.6; H, 9.93; N, 6.96. Found: C, 65.16;H, 10.06; N, 6.94.

The free l-aminomethyl adamantane melts at 128.5 C. and can be convertedto an acetyl derivative by treatment with acetic anhydride which, afterrecrystallization from n-hexane, melts at 123-124".

Analysis.Calcd. for C H ON: C, 75.31; H, 10.20; N, 6.76. Found: C,75.45; H, 9.97; N, 7.08.

Example 2 A solution of 17 parts of l-adamantoyl chloride in 150 partsof acetone is treated with 15 parts of a 40% aqueous solution ofmethylarnine at C. After complete addition, the mixture is warmed gentlyand diluted with Water. The crystalline l-N-methyl adamantanecarboxamide is isolated by filtration as 11.27 parts of material meltingat 137138 C. In an alternative synthesis of this compound, drymethylamine, 2 equivalents, is distilled into an ethereal solution ofadamantoyl chloride, 1 equivalent, and the resulting solution evaporatedto dryness. The product is washed thoroughly with water to remove thernethylammonium chloride formed and dried in vacuum to give a 96% yieldof l-N-methyl adaznantane carboxamide. A solution of 11 parts of thecrude amide in 100 parts of tetrahydrofuran is added slowly to asuspension of 2.4 parts of lithium aluminum hydride in 100 parts ofether. After complete addition, the mixture is refluxed for one hour,the solvent distilled ofl, and the residue subjected to steamdistillation. The steam distillate is extracted with cyclohexane, thecyclohexane solution dried with solid sodium hydroxide and dry hydrogenchloride passed into the solution. The solid l-(N-methylaminomethyl)adamantane hydrochloride is recrystallized fromethanol to give crystals melting at 324.5- 325 C. in a sealed capillary.

Analysis.Calcd. for C H NCl: N, 6.51. Found: N, 6.11.

Example 3 A solution of 19.85 parts of l-adamantoyl chloride in 100parts of dry diethyl ether is stirred at 0 C. and an ethereal solutionof 9 parts of dimethylamine added slowly. The mixture is then stirred atroom temperature for 30 minutes and evaporated to dryness. The residualsolid is triturated with water and extracted with ether. The etherealsolution is dried over anhydrous sodium sulfate and the ether removed.This gives 19.5 parts (94.2%) of 1-N,N-dimethyl adamantane carboxamidewhich melts at 76-78 C. The 19.5 parts of amide is dissolved in 100parts of ether and added slowly to a well stirred suspension of 4.5parts of LiAlH in 300 parts of ether. After complete addition thereaction is refluxed for 1 hour and the solvent removed. The residue issteam distilled to give 1-(N,N-dimethylaminomethyl)adamantane in thedistillate. The steam distillate is extracted with cyclohexane, theextract dried with sodium hydroxide and dry hydrogen chloride passedinto the solution. The yield of 1-(N,N-dimethylaminomethyl)adamantanehydrochloride is 17 parts or 84%. The crystals melt at 254 in a sealedcapillary after crystallization from methanol-ethyl acetate.

Analysis.--Calcd. for C H NCl: C, 68.20; H, 10.51; N, 6.1. Found: C,66.94; H, 10.57; N, 5.94.

Example 4 A solution of 19.85 parts of l-adamantoyl chloride is treatedwith 9 parts of ethylamine under the condi- 10 tions outlined in theprevious example to give 19.56 parts, 94.5%, of l-N-ethyl adamantanecarboxamide melting at 138 C.

A tetrahydrofuran solution of this amide is reduced with LiA1H asdescribed in the previous example. After removal of the organic solventthe residue is refluxed with water for 10 minutes to facilitatefiltration and filtered. Both the filtrate and the solid are extractedthoroughly with ether. The combined extracts are dried with sodiumhydroxide and hydrogen chloride passed into the solution. This gives19.68 parts (86% overall yield) of l-(N-ethylaminomethyl)adamantanehydrochloride. The melting point, after recrystallization from methanolis 356 C.

Analysis.Calcd. for C H NCI: C, 68.2; H, 10.51; N, 6.1. Found: C, 67.83;H, 10.43; N, 5.97.

Example 5 A solution of 19.85 parts of l-adamantoyl chloride in other isreacted with an ethereal solution of 12 parts of propylamine by theprocedure of Example 3 to give 21.38 parts of l-(N-propyl)adamantanecarboxamide melting at 140141 C. Twenty-one parts of this amide isreduced with LiAlH as shown in the previous example to give 19.4 partsof l-(N-propylamino-rnethyl)adamantane hydrochloride. Afterrecrystallization from methanol, this melts at 342 C.

Analysis.-Calcd for C H NCl: C, 69.1; H, 10.78; N, 5.76. Found: C,68.86; H, 10.93; N, 5.80.

Example 6 Under the conditions of the previous example, 19.85 parts ofl-adamantoyl chloride and 14.67 parts of diethylamine give 22.8 parts of1-N,N-diethyladamantane carboxamide, M.P. 6263 C.

This amide when reduced with LiAlH gives 22.7 parts of1-(N,N-diethylaminomethyl)adamantane hydrochloride. This, afterrecrystallization from ethyl acetatemethanol, melts at 240241 C.

Example 7 A solution of 5.8 parts of 3-carboxytricyclo[4.3.1.1 undecanein 10 parts of thionyl chloride is refluxed until hydrogen chlorideevolution ceases. The crude acid halide thus prepared is isolated bydistilling off the excess thionyl chloride under reduced pressure,adding a small amount of benzene and removing this under reducedpressure. The acid chloride is then dissolved in 200 parts of ether andan excess of dry methylamine passed into the stirred solution at 0 C.The reaction is then stirred for 30 minutes and diluted with water. Thelayers are separated, the ether layer washed with water and dried overcalcium chloride. Removal of the solvent gives 3.7 parts of whiteleaflets, melting at 133 C., of N-methyltricyclo [4.3. l.1 ]undecyl-3-carboxamide.

A solution of this amide in parts of tetrahydrofuran is added to asuspension of 2 parts of LiAlH in 100 parts of diethyl ether. Aftercomplete addition, the mixture is refluxed for one hour and the solventremoved by distillation. Water is added slowly to the dry residue andthe mixture then refluxed for ten minutes and filtered. Both the cooledfiltrate and the solid filter cake are extracted thoroughly with ether,the ethereal solution dried with sodium hydroxide and excess dryhydrogen chloride passed into the solution. The amine hydrochloridewhich precipitates is isolated by filtration and recrystallized frommethanolethyl acetate. A yield of 2.1 parts of 3 Nmethylaminomethyl)tricyclo[4.3.l.1 ]undecane HCl melting at 338 C., isobtained.

Example 8 The amine hydrochloride of Example 2, 5.4 parts, is dissolvedin 20 parts of pyridine and 5 parts of acetic anhydride is added. Themixture is warmed gently until a clear solution is obtained, then heatedon a steam bath for 30 minutes and diluted with cold water. The solidExample 9 A sample of B-carboxamidotricyclo [4.3.l.1 ]undecane isprepared by convertin the 3-carboxytricyclo[4.3.1. 1 ]undecane ofStetter, Ber., 92, 1629-1635 (1959), to

the acid chloride by treatment with thionyl chloride fol-- lowed bytreatment of the crude acid chloride with ammonia. The amide melts at180-181 C. after recrystallization from acetone.,The amide, 9.75 parts,is added in tetra hydrofuran solution, to 3 parts of lithium aluminumhydride suspended in 100 parts of ether. The mixture is refluxed onehour and the resulting amine is isolated as in Example 4. The product is6.5 parts of 3-(aminomethyl)tricyclo[4.3.1.1 ]undecane hydrochloride,M.P. 352- 352.5 C.

Example 10 A solution of 19.85 grams (0.10 mole) of l-adamantoylchloride in 100 milliliters of dry diethyl ether is stirred at C. and anethereal solution of 12.7 grams (0.15 mole) of piperidine is addedslowly. The mixture is stirred at room temperature for 30 minutes andevaporated to dryness. The residual solid is triturated with water andextracted with ether. The ethereal solution is dried over anhydroussodium sulfate and the ether removed to leave 1-adamantoylpiperidide. Asolution of 0.10 mole of l-adamantoylpiperidide in 100 milliliters ofether and added slowly to a well-stirred suspension of 4.5 grams oflithium aluminum hydride in 300 milliliters of ether. After completeaddition, the reaction is refluxed for 1 hour and the solvent removed.Then, the residue is refluxed with 250 milliliters of water for minutes,cooled, filtered, and both the filtrate and the solids are extractedthoroughly with ether. The combined extracts are dried with potassiumhydroxide, and then hydrogen chloride is passed into the solution. Theprecipitate is filtered and dried to give N-(LadamantylmethyDpiperidinehydrochloride.

Example 11 A mixture of 3.6 g. of magnesium turnings, a small crystal ofiodine,,1l ml. of anhydrous benzene and 1 ml. of absolute ethanol isheated until a reaction begins. Then heating is discontinued and amixture of 24.0 g. of diethyl malonate, 7.0 g. of absolute ethanol and30 ml. of benzene is added dropwise at a rate which causes thereactionmixture to reflux. After addition is completed, the mixture isheated at reflux until the magnesium has dissolved. The excess ethanolis removed by azeotropic distillation with some of the benzene. To theresultant solution of ethoxymagnesiumdiethylmalonate is added a solutionof 19.8 g. of l-adamantoyl chloride in 30 ml. of anhydrous benzene,dropwise, over a 50-minute period. The reaction mixture is refluxed foran additional hour, and then cooled in an ice bath. To the cold mixtureis added 50 g. of ice followed by suflicient 10% sulfuric acid to causetwo clear layers to appear. The layers are separated and the aqueouslayer is extracted with two 25-ml. portions of benzene. The extracts arecombined with the organic layer, washed with 30 ml. of water, and driedwith anhydrous sodium sulfate. The benzene is removed by vacuumconcentration at 40. A solution of 64 ml. of glacial acetic acid, 39 ml.of water and 7 ml. of concentrated sulfuric acid is added to the residue(32 g.), and the mixture is heated at reflux for 7 hours. Then it iscooled and poured into 350 ml. of water. The solid which separates isfiltered and dried, and then recrystallized from methanol-water mixtureto give 13.4 g. of White, crystalline adamantyl-(l) methyl ketone, M.P.53.5-55" C.

A mixture of 14 g. of hydroxylamine hydrochloride, 65 ml. of anhydrouspyridine and 65 ml. of anhydrous ethanol is heated on a steam bath untila clear solution is obtained. To this is added 13.4 g. of adamantyl-(l)methyl ketone, and the mixture is heated at reflux for 2 hours, thencooled. It is concentrated to dryness in a vacuum at 70, and the residueis suspended in 150 ml. of water and stirred well. The solids arefiltered and dried to yield 14.2 g. of adamantyl-( 1) methyl ketoneoxime, a white, crystalline compound melting at 180.5 182 C. This can berecrystallized from a dioxane-water mixture without affecting themelting point.

An 8.3-g. amount of adamantyl-(1)methyl ketone.

oxime is added to a mixture of 3.3 g. of lithium aluminum hydride in 150ml. of anhydrous tetrahydrofuran, and the mixture is stirred and heatedat reflux for 3 hours. It is cooled in an ice bath and the excess oflithium aluminum hydride is destroyed with a water-tetrahydrofuranmixture. Several ml. of 10% sodium hydroxide solution is added to aid inthe coagulation of the solids, which are removed by filtration, washedwith 50 ml. of chloroform, and discarded. The filtrate, which includesthe tetrahydrofuran solution and the chloroform solution, is saturatedwith dry hydrogen chloride and then concentrated to dryness in a vacuumat 50 C. The residue is placed in a separatory funnel and shaken with amixture of ml. of 10% sodium hydroxide and 300 ml. of ether. The aqueouslayer is discarded and the ether solution is dried over potassiumhydroxide pellets. Dry hydrogen chloride is passed into the ethersolution until precipitation is complete, and the resultant aminehydrochloride is filtered and dried. This crude salt is dissolved inwater, treated with excess 50% sodium hydroxide solution, and the freeamine is extracted with ether. The ether extract is dried over potassiumhydroxide pellets, decanted, and hydrogen chloride is passed in untilprecipitation is complete. The precipitate is filtered and dried toyield 5.6 g. of white, crystalline u-methyl-ladamantanemethylaminehydrochloride, M.P. 373375 C. (sealed tube).

Analysis.--Calcd. for C l-I NCl: C, 66.82; H, 10.20;

N, 6.49. Found: C, 66.52; H, 10.13; N, 6.38.

Example 12 Substitution of 21.3 g. of 3-tricyclo[4.3.1.1 ]-undecoylchloride for the 19.8 g. of l-adamantoyl chloride in Example 11 andrepetition of the procedure of that example leads to tricyclo[4.3.l.1]undecyl-(3) methyl ketone, then to tricyclo[4.3.1.1 ]undecyl-(3) methylketone oxime, and, after the reduction, to u-methyl-3- tricyclo [4.3 1.1 -undecanemethylamine hydrochloride.

Example 13 To a solution of 31.5 g. of l-adamantoyl chloride in 500 ml.of anhydrous ether under a nitrogen atmosphere is added, dropwise, ml.of commercial 3 M methyl magnesium bromide at a rate which maintains agentle reflux. The reaction mixture is heated for 1 hour after theaddition, then cooled. To decompose the metal complex, 300 ml. ofsaturated ammonium chloride is added. The ether layer is separated andthe aqueous layer is extracted with 100 ml. of chloroform. This extractis combined with the ether layer, and the mixture is dried withanhydrous magnesium sulfate and vacuum-concentrated to dryness at 35 C.The residue is steam-distilled until the distillate is no longer milky,about 3 liters of distillate being collected. On cooling, the steamdistillate crystallizes. The solids are filtered and dried to yield 26.9g. of a,a-dimethyl-l-adamantanemethanol, M.P. 77- 80 C.

A 35-m1. amount of concentrated sulfuric acid is added dropwise withcooling to hold the temperature below C. to 160 ml. of acetonitrile.Then, 21 g. of (1,0:- dimethyl-l-adamantanemethanol is added. Thetemperature is raised to 48 C. and maintained at 48 C. for 45 minutes.The reaction mixture is allowed to cool to room temperature and is thenslowly poured into 1000 ml. of ice water. The solidswhich separate arefiltered and dried to yield 24.2 g. of crude product. This is taken upin 500 ml. of ether and dry hydrogen chloride is bubbled into the ethersolution until no further precipitation occurs. The solids are filtered,dried, and placed in a separatory funnel containing 200 ml. of water and500 ml. of ether. This is shaken until the solids dissolve, and theaqueous layer is separated and discarded. The ether solution is driedwith anhydrous sodium sulfate and concentrated to dryness to give whitecrystals of N-acetyl-a,a-dimethyll-adamantanernethylamine.

A mixture of 2.0 g. of N-acetyl-a,a-dimethyl-ladamantane methylamine, 10g. of potassium hydroxide and 40 m1. of methanol is heated at 225 C. ina sealed tube for 18 hours, then cooled. The tube contents are added to100 ml. of water, and the mixture is extracted with two 50-ml. portionsof ether. The extracts are combined, dried with potassium hydroxidepellets, and dry hydrogen chloride is bubbled in until precipitation iscomplete. The precipitate is filtered and dried to give 1.8 g. of crudesalt. This is dissolved in 80 ml. of water and treated with an excess of50% sodium hydroxide. The amine precipitates, and is filtered and dried,M.P. 103- 105 C. This is taken up in ether and precipitated withhydrogen chloride. The hydrochloride is filtered and dried. The meltingpoint of a,or-dimethyl-1 adamantanemethylamine hydrochloride is 340-345C. (sealed tube).

Analysis.-Calcd. for C H NCl: C, 67.98; H, 10.45; N, 6.10. Found: C,67.75; H, 10.35; N, 6.17.

Example 14 Substitution of 33.7 g. of 3-tricyclo[4.3.1.1 ]undecoylchloride for the 31.5 g. of l-adamantoyl chloride in Example 13 andrepetition of the procedure of that example leads toa,a-dimethyl-3-tricyclo[4.3.1.l ]undecanemethanol, then toN-acetyl-u,ot-din1ethyl-3-tricyclo[4.3.1.1 undecanemethylamine, and,after hydrolysis, to aux-(limethyl-3-tricyclo[4.3.l.1 Jundecanemethylamine hydrochloride.

Example 15 To a mixture of 1.5 g. of lithium aluminum hydride in 100 ml.of anhydrous diethylene glycol, dimethyl ether is added 4.1 g. ofN-acetyl-a,a-dimethyl-1-adamantanemethylamine, prepared in Example 13.The reaction mixture is stirred and heated at reflux for 3 hours, thencooled in an ice bath. The excess lithium aluminum hydride is decomposedby adding wet diethylene glycol, dimethyl ether. Several ml. of 10%sodium hydroxide is added to coagulate the precipitate, which is thenfiltered and washed with 50 ml. of ether. The filtrate is treated withdry hydrogen chloride until no additional precipitate forms. This isfiltered, dissolved in 100 ml. of water, and an excess of 50% sodiumhydroxide is added. The mixture is extracted with three -ml. portions.of ether, and the ether extracts are combined, dried with potassiumhydroxide pellets, and treated With hydrogen chloride untilprecipitation is complete. This precipitate is filtered and dried toyield 3.2 g. of N-ethyl-a,a-dimethyll-adamantanemethylaminehydrochloride, M.P. 276-279 C. (sealed tube).

Analysis.Calcd. for C H NCl: C, 69.91; H, 10.87; N, 5.44. Found: C,69.33; H, 11.00; N, 5.67.

Ex mple 16 Substitution of 4.5 g. of N-acetyl-a,a-dimethyl-3-tricyclo[4.3.l.1 ]undecanemethylamine, prepared in Example 14, for the4.1 g. of N-acetyl-u,u-dimethyl-1- adamantanemethylamine and repetitionof the procedure of Example 15, leads toN-ethyl-a,u-dimethyl-3-tricyclo- [4.3.1.1 ]undecanemethylaminehydrochloride.

Example 17 A solution of diethyl cadmium in benzene is prepared byadding 19.6 g. of powdered anhydrous cadmium chloride over a 5-minuteperiod to 0.2 mole of ethyl magnesium bromide in ml. of anhydrous etherat ice bath temperature. The mixture is heated at reflux with vigorousstirring for 30 minutes. Then, the ether is removed by distillation on asteam bath, and 65 ml. of benzene is added to the nearly dry, brown,pasty residue. Distillation is continued until the vapor temperature ofthe distillate reaches 61 C. An additional 100 ml. of benzene is addedto the diethyl cadmium solution, and the solution is again heated toreflux. Heating is discontinued, vigorous stirring is begun, and asolution of 19.8 g. of l-adamantoyl chloride is added as rapidly as theexothermic reaction will allow. Refluxing and stirring is continued foran additional 45 minutes. The reaction mixture is cooled in an ice bathand 200 g. of water and ice is added, followed by ml. of 20% sulfuricacid. The benzene layer is separated and the aqueous layer is extractedwith 75 ml. of benzene. The benzene solutions are combined, dried Withanhydrous sodium carbonate, and the benzene is removed by vacuumconcent-ration at 50 to yield a liquid residue. This crystallizes oncooling, giving 21.6 g. of adamantyl-(l) ethyl ketone, M.P. 30.5-32.5 C.

A mixture of 75 ml. of anhydrous ethanol, 75 ml. of anhydrous pyridine,16 g. of hydroxylamine hydrochloride and 16.0 g. of adamantyl-(l) ethylketone is heated at reflux for 2 hours and then vacuum concentrated tosemi-dryness .at 80 C. A ZOO-ml. amount of water is added, and themixture is again concentrated to semidryness. The residue is suspendedin 300 ml. of water, and the solids are filtered. The melting point ofthis crude material is -177 C. Recrystallization from a mixture ofdioxane and acetonitrile gives 10.3 g. of white, crystallineadamantyl-(l) ethyl ketone oxime, M.P. 177- 179 C.

A 7.7-g. quantity of adamantyl-(l) ethyl ketone oxime is added to amixture of 3.0 g. of lithium aluminum hydride and 150 ml. of anhydrousdiethylene glycol dimethyl ether, and the mixture is stirred and heatedat reflux for three hours. It is cooled to 10 C. with an ice bath andthe excess lithium aluminum hydride is destroyed with wet diethyleneglycol dimethyl ether. Five ml. of 10% sodium hydroxide is added tocoagulate the solids, which are then filtered, washed with 50 m1. ofether and discarded. The filtrate is saturated with dry hydrogenchloride and vacuum concentrated until precipitation is complete. Theconcentrated filtrate is cooled and the solids are filtered, washed withether and dried. The dried salt is dissolved in 150 ml. of Water and thesolution is treated with excess 50% sodium hydroxide and extracted withtwo 50-ml. portions of ether. The ether extracts are combined, driedwith potassium hydroxide pellets, and treated with dry hydrogen chlorideuntil precipitation is complete. The precipitate is filtered and driedto give 5.2 g. of white, crystalline a-ethyl-ladamantanemethylaminehydrochloride, M.P. 278-282" C. (sealed tube).

Analysis.-Calcd. for C H NCl: C, 67.99; H, 10.45; N, 6.10. Found: C,68.55; H, 10.48; N, 6.14.

Example 18 Substitution of 21.3 g. of 3-tricyclo[4.3.l.l ]undecoylchloride for the 19.8 g. of l-adamantoyl chloride in Example 17, andrepetition of the procedure of that example leads to tricyclo[4.3.l.l]undecyl-(3) ethyl ketone, then to tricyclo [4.3.1.1 ]undecyl-( 3) ethylketone oxime, and, after the reduction, to a-ethyl-3-tricyclo [4.3.1.1]undecanemethylamine hydrochloride.

Example 19 Use of 0.10 mole of 3-tricyclo[4.3.1.l ]undecoylchlo- Example21 Use of 0.10 mole of 3-tricyclo[4.3.1.1 ]undecoylchloride (see Example7) and 0.15 mole of diallylamine instead of the l-adamantoyl chlorideand piperidine in the procedure of Example 10 gives3-(N,N-di-allylaminomethyl)tricyclo [4.3.1.1 ]undecane hydrochloride.

Example 22 Use of 0.15 mole of propargylamine instead of the 0.15 moleof piperidine in Example 10 gives l-(N-propargylaminomethyhadamantanehydrochloride.

Example 23 Use of 0.15 mole of cyclopropylmethylamine instead of the0.15 mole of piperidine in Example 10 gives l-(N-cyclopropyl-methylaminomethyl)adamantane hydrochloride.

Example 24 Use of 0.10 mole of 3-tricyclo[4.3.1.1 ]undecoylchloride (SeeExample 7) and 0.15 mole of cyclobutylamine instead of the l-adamantoylchloride and piperidine in the procedure of Example 10 gives3-(N-cyclobutylaminoethyl) -tricycl [4.3. 1 1 undecane hydrochloride.

Example 25 A milliliter flask with magnetic stirrer and reflux condenseris charged with 0.050 mole of l-(aminomethyl) adamantane, 6.13 grams(0.050 mole) of ethyl chloroacetate, 5.00 grams (0.060 mole) of sodiumbicarbonate and 20 milliliters of methanol. The insoluble material isfiltered and the filtrate is evaporated to dryness. The residue isdissolved in 60 millilitersof 1N hydrochloric acid, and 10 millilitersof, 70% perchloric acid is added. The precipitated perchlorate salt isfiltered, Washed with cold water, and dried. The free base isregenerated with 10% sodium hydroxide and distilled to remove unchangedstarting material. The higher boiling fraction is N( l-adamantylmethyl)glycine, ethyl ester.

Example 26 fate, and concentrated in vacuo to givel-[N-Z-diethylaminoethyl) -N-methylaminomethyl] adamantane.

Example Product of Example 16 Example 27 A flask equipped with aDean-Stark water separator is charged with 0.10 mole. of3-(aminomethyl)tricyclo- [4.3.1.l ]undecane (see Example 9), 15.4 grams(0.10 mole) of freshly distilled benzaldehyde, and 50 milliliters oftoluene. The solution is allowed to reflux for 45 hours. The toluene isevaporated and the residue is recrystallized to giveN-(3-tricyclo[4.3.1.1 ]undecylmethyl)benzaldimine.

Example 28 A solution of 0.5 mole of l-(aminomethyl)adamantane in 120milliliters of tetrahydrofuran and 30 milliliters of Water is chargedinto a 400 milliliter stainless steel autoclave and 5.0 grams (0.11mole) of ethylene oxide is injected. The autoclave is heated to C. for24 hours after which time it is cooled and cautiously vented. Solvent isremoved at reduced pressure, and the residue is extracted with ether.The ether extract is dried with anhydrous potassium carbonate. Solventis removed at reduced pressure and the residue is subjected tosublimation at 100 C./20 mm. in order to remove unreactedl-(aminomethyl)adamantane. The residue from the sublimation is distilledunder vacuum to yield 1-[N-(2-hydroxyethyl)aminomethyl]adamantane.

Example 29 A solution of 0.10 mole of 1-(aminomethyl)adamantane inmilliliters of 98% formic acid is allowed to stand 48 hours at roomtemperature. The formic acid is removed by concentration in vacuo toleave the residue, l-(formamidomethyl)adamantane.

Alternatively, this compound is prepared by refluxing 0.05 mole ofl-(aminomethyl)adamantane for 19 hours in 25 ml. of butyl formate. Theexcess butyl formate is removed by vacuum concentration to leave aresidue of l-(formamidomethyl)adamantane.

Example 30 A suspension of 0.1 mole of 3-(aminomethyl)tricyclo- [4.3.1.1]undecane in 100 milliliters of ice water is placed in a 500 milliliterflask equipped with mechanical stirrer and thermometer. The flask iscooled in an ice bath, and 142 grams of 5.25% sodium hypochloritesolution (commercial Chl0rox) is added at such a rate that thetemperature does not exceed 10 C.

After the addition is complete the ice bath is removed and the mixtureis stirred for 30 minutes. It is then extracted with three 50 milliliterportions of ether. The combined ether extracts are dried over calciumchloride. The solution is filtered and solvent is removed under vacuumto yield 3-(N-chloroaminomethyl)tricyclo[4.3.1.1 undecane.

Example 31 A mixture of 0.10 mole of 1-(aminomethyl)adaman tame and 9.87grams (0.10 mole) of 38% hydrochloric acid in 100 milliliters of wateris concentrated in vacuo at 60 C. The resulting salt,l-(aminomethyl)adamantane hydrochloride, is dried in vacuo at 60 C.

Examples 32 through 40 Example 18 is repeated, substituting thefollowing indicated reactants for those of that example, .to obtain theindicated product.

Acid Product 1 (free base) 2 (free base) 0.10 mole). 3 (free base) (0.10mole) 4 (free base) (0.10 mole). 5 (free base) (0.10 mole). 6 (treebase) (0.10 mole).

7 (0.10 mole) 8 (0.10 mole) 9 (0.10 mole) phosphoric acid (0.10 mole)Sulfuric acid (0.050 mole) Tartan'c acid (0.10 mole) Tartaric acid(0.050 mole) Maleic acid (0.10 mole) Acetic acid (0.10 mole) Succinicacid (0.050 mole) Mandelic acid. (0.10 mole) Lactic acid (0.10 mole) 1 7Example 41 A solution of 0.20 mole of l-(aminoethyl)adamantanehydrochloride in 100 milliliters of water is added to a solution of 0.10mole of pamoic acid, disodium salt [44'- methylenebis(3-hydroxy-2naphthoic acid), disodium salt] in 500 milliliters ofwater. The resulting precipitate is filtered, washed well with water,and dried in vacuo to give l-(aminomethyl)adamantane, pamoate.

Example 42 Carbon dioxide is passed into a solution of 0.10 mole ofl-(aminomethyl)adamantane in 100 milliliters of ethyl ether untilprecipitation is complete. The precipitate is filtered and dried invacuo to give l-(aminoethyl) adamantane, bicarbonate.

The preceding examples can be repeated substituting equivalent amountsof appropriate starting materials toobtain other compounds of thisinvention including those listed hereinbefore.

The compounds of this invention can be administered in the antiviraltreatment according to this invention by any means that effects contactof the active ingredient compound with the site of virus infection inthe body. It will be understood that this includes the site prior toinfection setting in as well as after. For example, administration canbe parenterally, that is subcutaneously, intraveneously,intramuscularly, or intraperitoneally. Alternatively or concurrently,administration can be by the oral route.

The dosage administered will be dependent upon the virus being treated,the age, health and weight of the recipient, the extent of infection,kind of concurrent treatment if any, frequency of treatment, and thenature of the effect desired. Generally, a daily dosage of activeingredient compound will be from about 1 to 50 milligrams per kilogramof body weight, although lower, such as 0.5 milligram, per kilogram orhigher amounts can be used. Ordinarily, from 1 to 20 and preferably 1 to10 milligrams per kilogram per day, in one or more applications per dayis effective to obtain the desired result.

The active ingredient of this invention can be employed in usefulcompositions according to the present invention in such dosage forms astablets, capsules, powder packets, or liquid solutions, suspensions, orelixirs, for oral administration or liquid solutions for parenteral use,and in certain cases, suspensions for parenteral use (exceptintravenous). In such compositions the active ingredient will ordinarilyalways be present in an amount of at least 0.5% by weight based on thetotal weight of the composition and not more than 90% by weight.

Besides the active ingredient of this invention the antiviralcomposition will contain a solid or liquid non-toxic pharmaceuticalcarrier for the active ingredient.

In one embodiment of a pharmaceutical composition of this invention, thesolid carrier is a capsule which can be of the ordinary gelatin type. Inthe capsule will be from about 30-60% by weight of a compound ofFormulas 1 and 2 and 70-40% of a carrier. In another embodiment, theactive ingredient is tableted with or without adjuvants. In yet anotherembodiment, the active ingredient is put into powder packets andemployed. These capsules, tablets and powders will generally constitutefrom about 5% to about 95% and preferably from 25% to 90% by weight.These dosage forms preferably contain from about 5 to about 500milligrams of active ingredient, with from about 25 to about 250 mostpreferred.

The pharmaceutical carrier can, as previously indicated, he a sterileliquid such as water and oils, including those of petroleum, animal,vegetable or synthetic origin, for example peanut oil, soybean oil,mineral oil, sesame oil, and the like. In general, water, saline,aqueous dextrose (glucose) and related sugar solutions and glycols suchas propylene glycol or polyethylene glycols are preferred liquidcarries, particularly for injectible solutions. Sterile 18 injectiblesolutions such as saline will ordinarily contain from about 0.5% to 25%,and preferably about 1 to 10% by weight of the active ingredient.

As mentioned above, oral administration can be in a suitable suspensionor syrup, in which the active ingredient ordinarily will constitute fromabout 0.5 to 10%, and preferably about 2 to 5%, by weight. Thepharmaceutical carrier in such composition can be a Watery vehicle suchas an aromatic water, a syrup or a pharmaceutical mucilage.

Suitable pharmaceutical carriers are described in Rem ingtons Practiceof Pharmacy by E. W. Martin and E. F. Cook, a well known reference textin this field.

In addition to the exemplary illustrations above, the following examplesfurther explain the present invention:

Example 43 A large number of unit capsules are prepared by fillingstandard two-piece hard gelatin capsules weighing about 50 milligramseach with 50 milligrams of powdered 1- (aminoethyl)adamantane,hydrochloride, 125 milligrams of lactose and 1 milligram of Cab-o-sil.

Example 44 Example 43 is repeated except that soft gelatin capsules areused and powdered l-(aminomethyl)adamantane is first dissolved inmineral oil.

Example 45 Example 43 is repeated except that the dosage unit is 50milligrams of active ingredient, 5 milligrams of gelatin, 1.5 milligramsof magnesium stearate and milligrams of lactose, mixed and formed into atablet by a conventional tableting machine. Slow release pills ortablets can also be used, .by applying appropriate coatings. A sugarcoating may be applied to increase palatability.

Example 46 A parenteral composition suitable for administration byinjection is prepared by stirring 5% by weight of the active ingredientof Example 43 in sterile aqueous 0.9% saline.

A large variety of compositions according to this invention can thusreadily be made by substituting other compounds of thisinvention, andincluding specifically but not limited to compounds of this inventionthat have specifically been named hereinbefore. The compounds will "beused in the amounts indicated in accordance with procedures well knownand described in the Martin and Cook text mentioned above. f

Compounds within the scope of Formulae 1 and 2 of the invention areanti-viral agents in domestic animals and livestock. As an illustration,compounds within the'scope of Formulae 1 and 2 are effective againstswine influenza and an embodiment of the intlention, therefore, is acontrol of this infection by incorporating an active ingredient compoundin the diet of the affected animal. For most purposes, an amount ofactive compound will be used to provide from about 0.0001% to 0.1% byweight of the active compounds based on the total weight of feed intake.Preferably, from 0.001% to 0.02% by weight will be used.

In like manner novel and useful compositions are pro vided by thisinvention which comprise at least one active ingredient compound withinthe scope of this invention in admixture with an animal feed.Descriptions of suitable feeds can be found in the book Feeds andFeeding by Frank B. Morrison, published by the Morrison PublishingCompany of Ithaca, N.Y., 1948, 21st edition. The selection of theparticular feed is within the knowledge of the art and will depend ofcourse on the animal, the economics, natural materials available, thesurrounding circumstances and the nature of the effect desired, as willbe readily understood.

A particularly important composition according to this feature of theinvention is a concentrate, suitable for preparation and sale to afarmer or livestock grower for addition to the animals feedstuffs inappropriate proportion. These concentrates ordinarily comprise about0.5% to about 95% by weight of the active ingredient compound togetherwith a finely divided solid, preferably flours, such as wheat, corn,soya bean and cottonseed. Depending on the recipient animal, the solidadjuvant can be ground cereal, charcoal, fullers earth, oyster shell andthe like. Finely divided attapulgite and bentonite can be used, theselatter materials also acting as solid dispersing agents.

The feed compositions, as well as the just-described concentrates, canadditionally contain other components of feed concentrates or animalfeeds, as will be readily understood. Other particularly importantadditives include proteins, carbohydrates, fats, vitamins, minerals,antibiotics, etc.

The disclosure herein should not be taken as a recommendation to use thedisclosed invention in any Way without full compliance with US. Food andDrug laws and other laws and governmental regulations which may beapplicable.

The above and similar examples can be carried out in accordance with theteachings of this invention, as will be readily understood by personsskilled in the art, by substitution of components and amounts in placeof those specified. Thus, the foregoing detailed description has beengiven for clearness of understanding only and no unnecessary limitationsare to be understood therefrom.

The invention claimed is:

1. A compound selected from the group consisting of those of the formula20 and A is hydrogen, and

wherein X and Y are each hydrogen, methyl, or ethyl; and R is m -N H2).

where n is an integer of from 2 through 6; NR R or --N=CHR wherein R ishydrogen; alkyl of 1 through 6 carbon atoms; mono-substituted alkyl of 1through 6 carbon atoms where the substituent is hydroxy, alkoxy of 1through 2 carbon atoms, NH --NHR or NR R where R, and R are each alkylof 1 through 4 carbon atoms; alkenyl of 2 through 6 carbon atoms;alkynyl of 2 through 6 carbon atoms; cyclopropyl; cyclobutyl;cyclopropylmethyl; or cyclobutylmethyl; R is R chlorine; bromine;formyl; -CH COOH;

CH COOCH or -CH COOC H with the proviso that when R is alkenyl oralkynyl having the unsaturated bond in the l-position, R is alkyl of 1through 6 carbon atoms or mono-substituted alkyl of 1 through 6 carbonatoms where the substituent is hydroxy, alkoxy of 1 through 2 carbonatoms,

-NH NHR and --NR R and R is hydrogen, alkyl of 1 through 5 carbon atoms,

phenyl, naphthyl or furyl; and non-toxic, acid-addition salts of thecompounds of said formula. 2. l-(N,N dimethylarninomethyl)adamantanehydrochloride.

References Cited Stetter et al., Ber. Deut. Chem, vol. 96, pp. 550-55,February 1963.

CLLARLES B. PARKER, Primary Examiner.

N. WIC ZER P. C. IVES, Assistant Examiners.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE OF THE FORMULA